Structure of the Yersinia pestis FabV enoyl-ACP reductase and its interaction with two 2-pyridone inhibitors

Maria W. Hirschbeck, Jochen Kuper, Hao Lu, Nina Liu, Carla Neckles, Sonam Shah, Steffen Wagner, Christoph A. Sotriffer, Peter J. Tonge, Caroline Kisker

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The recently discovered FabV enoyl-ACP reductase, which catalyzes the last step of the bacterial fatty acid biosynthesis (FAS-II) pathway, is a promising but unexploited drug target against the reemerging pathogen Yersinia pestis. The structure of Y. pestis FabV in complex with its cofactor reveals that the enzyme features the common architecture of the short-chain dehydrogenase reductase superfamily, but contains additional structural elements that are mostly folded around the usually flexible substrate-binding loop, thereby stabilizing it in a very tight conformation that seals the active site. The structures of FabV in complex with NADH and two newly developed 2-pyridone inhibitors provide insights for the development of new lead compounds, and suggest a mechanism by which the substrate-binding loop opens to admit the inhibitor, a motion that could also be coupled to the interaction of FabV with the acyl-carrier protein substrate.

Original languageEnglish (US)
Pages (from-to)89-100
Number of pages12
JournalStructure
Volume20
Issue number1
DOIs
StatePublished - Jan 11 2012
Externally publishedYes

Fingerprint

Yersinia pestis
Oxidoreductases
Acyl Carrier Protein
Coenzymes
NAD
Catalytic Domain
Fatty Acids
Pharmaceutical Preparations
2-hydroxypyridine
Lead
short chain trans-2-enoyl-CoA reductase

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Hirschbeck, M. W., Kuper, J., Lu, H., Liu, N., Neckles, C., Shah, S., ... Kisker, C. (2012). Structure of the Yersinia pestis FabV enoyl-ACP reductase and its interaction with two 2-pyridone inhibitors. Structure, 20(1), 89-100. https://doi.org/10.1016/j.str.2011.07.019

Structure of the Yersinia pestis FabV enoyl-ACP reductase and its interaction with two 2-pyridone inhibitors. / Hirschbeck, Maria W.; Kuper, Jochen; Lu, Hao; Liu, Nina; Neckles, Carla; Shah, Sonam; Wagner, Steffen; Sotriffer, Christoph A.; Tonge, Peter J.; Kisker, Caroline.

In: Structure, Vol. 20, No. 1, 11.01.2012, p. 89-100.

Research output: Contribution to journalArticle

Hirschbeck, MW, Kuper, J, Lu, H, Liu, N, Neckles, C, Shah, S, Wagner, S, Sotriffer, CA, Tonge, PJ & Kisker, C 2012, 'Structure of the Yersinia pestis FabV enoyl-ACP reductase and its interaction with two 2-pyridone inhibitors', Structure, vol. 20, no. 1, pp. 89-100. https://doi.org/10.1016/j.str.2011.07.019
Hirschbeck, Maria W. ; Kuper, Jochen ; Lu, Hao ; Liu, Nina ; Neckles, Carla ; Shah, Sonam ; Wagner, Steffen ; Sotriffer, Christoph A. ; Tonge, Peter J. ; Kisker, Caroline. / Structure of the Yersinia pestis FabV enoyl-ACP reductase and its interaction with two 2-pyridone inhibitors. In: Structure. 2012 ; Vol. 20, No. 1. pp. 89-100.
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